Scott McPherson's Web Presence

The current situation in South Asia:

Over half of Bangladesh's political divisions are overrun by H5N1 in poultry.  Bangladesh, India and Pakistan have all created "isolation wards" for what they assume to be an eventual stream of bird flu-infected farmers and cullers.  India and Bangladesh, two nations that are constantly feuding, skirmishing and even occasionally warring over disputed border territory, suddenly realize there is no border when it comes to H5N1 and begin cooperating with each other. 

India's culling attempts are insufficient to stop this latest and worst outbreak of H5N1 in poultry in the nation's history.  The virus may have spread to other states neighboring West Bengal -- plus one state not so close, specifically the port city of Chittagong.  Culling in states neighboring West Bengal is underway, now under mandate from the Congress of India.

Experts argue over whether there is, or is not, H5N1 now in human hosts.  And the WHO is trying valiantly to determine if this fertile human Petri dish of a region will spawn the Next Pandemic.

So to say the situation in the South Asian region is bleak is to say the 1972 Miami Dolphins were simply happy at the outcome of the Super Bowl.  In other words, a massive understatement of the situation.

Of course, there are suspected cases.  A few cullers in hospital in Kolkata (Calcutta); a few elsewhere.  There are legitimate concerns regarding the accuracy of the tests being administered to the suspected infected.  And that is one reason why the WHO is on the ground there, making sure that everyone does their due diligence. 

I can only assume that St. Jude (not the hospital -- I mean St. Jude, the Patron Saint of Lost Causes, and the saint the hospital is named for) is in the region, working overtime for the benefit of all.  Why?  The good news in the bad news is that, at least so far, there have been no confirmed cases of H5N1 in humans.  Considering the size of the poultry cull, which almost certainly will reach to tens of millions of birds in total between India, Pakistan, Bangladesh and Turkey, to not have detected H5N1 in humans so far is nothing short of miraculous.  And miracles are the province of the saints, right?

It's as good an explanation as any I can come up with, or have heard up to now.

The weekend headlines shrieked "Scientists Make Bird Flu Breakthrough!" 

Well, not really a breakthrough on fighting the virus itself; more like a breakthrough on finding ways to more safely handle the H5N1 virus without accidentally triggering the next Stephen King novel.  If you search this Blogsite for my ongoing series "When Labs Attack," you will read horror story after horror story regarding how lab accidents can, and frequently do infect people, animals and the environment. 

One example: Just a few months ago, CSIRO workers in Australia were exposed to H5N1 when they all forgot to properly configure their canisters of air.  They are all fine, thanks for asking, but still the incident could have introduced the virus into the Australian nation. 

In this weekend's story,  Professor Mark von Itzstein and his team at the Institute for Glycomics at Australia's Griffith University worked with the very capable Professor Malik Peiris and his team at Hong Kong University's Institut Pasteur.  Peiris, for the uninitiated, is a protege of Dr. Robert Webster, the Pope of Influenza.   Besides his work on H5N1, he is also very well-known for his work in containing the SARS virus. 

The report that these seasoned viral researchers had discovered a way to slip the H5N1 virus into a protective envelope of a "virus-like particle" for safer examination is welcome news.

But I think the real message of that story was contained in the concluding paragraphs of the story which I found at: http://www.news.com.au/story/0,23599,23149404-1702,00.html . From the news.com.au story:

Prof von Itzstein, who helped to develop the influenza drug Relenza, said it was hoped the breakthrough could help to "crack the code" of the deadly H5N1 avian influenza virus.

OK, now here comes the most important part of the entire story:

The professor said the H5N1 virus had evolved to the stage where it could be transmitted from birds to humans, with evidence mounting that limited human-to-human transmission could also occur.

My friend Dr. Mike Osterholm was in Bangkok at that bird flu confab in late January, trying valiantly to convince the global press corps to stop writing about Beckham and Britney and start writing about something that will eventually happen, has happened with historical certainty ever since the Chinese domesticated ducks some 4,000+ years ago, and will absolutely keep happening, no matter how arrogant we are about our "superiority" over bugs. And that something is an influenza pandemic in the Just-in-Time 21st Century.

Professor von Itzstein is a man whose work has created the only antiviral that has not (yet) developed resistance in Influenza A.  He has studied H5N1 as much as any other scientist, perhaps including those intrepid people who work with Webster, Peiris and Oxford.  And he is telling us the "evidence is mounting" that the H5N1 virus is evolving, or adapting, or mutating, or whatever you want to call it.  Whatever you call it, it is heading for Humanity.  Slouching toward Bethlehem to be born, if you prefer Yeats.  And considering Bethlehem's strategic location and proximity to human and avian H5N1 cases, perhaps eerily prophetic.

Are we listening? 

I do much of my strategic thinking in decidedly NON-strategic places (loo, shower, etc.),  So it was that this morning, whilst showering, I remembered my blog of October 4, 2007, regarding the Swedish discovery that Tamiflu does not break down in municipal water supplies.

A specific news article stated:

Oct. 3 (Bloomberg) -- Roche Holding AG's Tamiflu persists in waste water, which may make the drug a less effective weapon in an influenza pandemic, Swedish researchers said.

The medicine's active ingredient, oseltamivir carboxylate, is excreted in the urine and feces of those taking it. Scientists at Sweden's Umea University found the drug isn't removed or degraded in normal sewage treatment, and its presence in waterways may allow flu-carrying birds to ingest it and incubate resistant viruses.

My post is at: http://www.scottmcpherson.net/journal/2007/10/4/killing-two-birds-with-one-stone.html and I hope you all periodically go back and search my blogs, in case my short-term memory ever malfunctions!

The reason why I bring it up is that Japan takes enough Tamiflu to make Roche very, very happy.  Yet, despite the theoretical presence of lots of peed-out Tamiflu in its wastewater systems, there is no evidence of Japanese H1N1 with the Tamiflu-resistant gene H274Y.  This would further supprt the theories of Dr. Henry Niman and others that this H1N1 mutation is not the result of a mutation derived from people taking mass quantities of Tamiflu.

It does, by proxy, support the theory that the H274Y gene was picked up via some recombination event elsewhere(s), and then came to Europe and North America via human contact.  It may also point us toward reservoirs of excreted Tamiflu in wastewater and, in some remote corners of the world, drinking water commingled with drinking water, in the vicinity of Tamiflu blankets.  Wherever a Tamiflu blanket is applied, are we checking the waste/groundwater to see how much residual antiviral is still active?  Could a combination of excreted Tamiflu in Indonesian, Egyptian, German, Mongolian, Chinese, and Egyptian lakes be a source of Tamiflu-resistant H5N1, incubated and then carried by migrating birds?

So I just wanted to share that thought, link the wastewater discovery of October with the current debate, and move on.  Now I must go and do more strategic thinking.  Now what did you say your name was?

My first read every morning when I sit in front of the computer is www.recombinomics.com, the Website run by Dr. Henry Niman.  Dr. Niman has some very interesting information regarding the H274Y Tamiflu-resistant mutation that is the subject of an increasing number of media reports over the past few days.  Even the New York Times and AP have picked up on the Helen Branswell/Canadian Press story of this week.

Here's what is peculiar:  Normally, you would expect Tamiflu-resistant H1N1 influenza to show up in areas where Tamiflu is prescribed.  But that is not the case here!  There are no known cases of H1N1 with the H274Y mutation in Japan, where Tamiflu is habitually overprescribed; and 70% of H1N1 is showing Tamiflu resistance in distant Norway, where Tamiflu is rarely, if ever, prescribed.  Quite a conundrum.

Dr. Niman believes that Tamiflu-resistant H1N1 with the H274Y mutation has already been detected in these US isolates:

ISDN282211  A/Hawaii/21/2007  H1N1  
ISDN282224  A/Hawaii/28/2007  H1N1  
ISDN282222  A/Hawaii/28/2007  H1N1  
CY027037      A/Kansas/UR06-0104/2007  H1N1  
ISDN282240  A/Minnesota/23/2007  H1N1  
ISDN263890  A/Texas/31/2007  H1N1 

According to Dr. Niman,

The above comments describe the appearance of the oseltamivir resistance marker, H274Y, in recent H1N1 isolates in Europe. 

However, a search of public sequences identifies H274Y suddenly appearing in 2007 H1N1 isolates from the United States (see list below.  The number of complete human influenza sequences has grown steadily, largely because of the NIAID influenza sequencing project.  At the Los Alamos sequence database, there are 1030 N1 sequences from H1N1 human isolates.  340 are from 2007 and all of the sequences below are from 2007.  Thus, although the percentage of samples was low, all were from 2007 and all were Solomon Island-like.

In the United States the change was in the Solomon Islands variant, which links back to Asia, where the identical change has been seen in H5N1 from patients treated with Tamiflu, as well as birds, including wild birds in Astrakhan in 2005.

These Solomon-Island lake sequences trace back to Asia, where Tamiflu blankets are frequently applied in the treatment of H5N1.  The N1 in H5N1 has donor sequences for human N1 in the region adjacent to the acquisition which generates H274Y, which is the precise change found in the most common form of oseltamivir resistance in H5N1 patients, primarily in Vietnam.

The two complete commentaries from Dr. Niman can be found at:

http://www.recombinomics.com/News/01290802/H1N1_Tamiflu_US.html

http://www.recombinomics.com/News/01300804/H1N1_H274Y_H5N1.html

Remember that the "A" refers to Influenza A, next comes the location where the virus was first typed, then the lab number, then the year, and then the subtype. 

Now, over at FluTrackers, the forum is as lively as ever.  And speculation centers around the actual inner workings of Tamiflu itself.  I am treading dangerously close to incompetence if I speculate any further, having reached the edge of my envelope on the surface properties of N1 vs. N2 subtypes of neuranimidase and their susceptibility to Tamiflu versus Relenza.  So I will simply give you the link and let you follow the bouncing ball:

http://www.flutrackers.com/forum/showthread.php?t=51648

So what does this mean?  It means that Tamiflu is still the #1 arrow in the quiver against pandemic flu.  It also means the people who make Relenza can rejoice somewhat, because it ups the ante for buying their product. 

But the deeper meaning is this: After years and years of use, the sudden appearance of this genetic marker in seasonal H1N1 has to be the result of a relatively recent series of developments.   Tamiflu resistance had to be acquired by H1N1.  The most likely place for it to have done so is in Asia, or Egypt.  Or both: There are compelling arguments for both, as we see geographically distinct Hawaii, Kansas and Minnesota isolates showing the mutation.  And talk about geographically distinct!  Again, from Branswell's story:

Eight of 81 H1N1 viruses tested carry the H274Y mutation - one each from British Columbia and Newfoundland and Labrador, and six from Ontario. Plummer said that total includes one virus (from British Columbia) recovered from a child who is believed to have been infected in Sudan.

That means this mutation is all over the place!  It could have come from anywhere.  But it is appropriate to zero in on the areas where Tamiflu resistance is most likely to be manufactured:  Wherever a Tamiflu blanket has been applied to try and quell an H5N1 outbreak.  Dr. Niman makes a compelling argument that these Tamiflu blankets may have spawned this mutation.

The theory is that H5N1 segments recombined with H1N1 seasonal flu to produce a new, Tamiflu-resistant substrain of H1N1.  Also keep in mind that the Southeast Asian strain of H5N1 is of a different clade (Fujian) than the Egyptian strain (Qinghai), so Tamiflu resistance would either have been conferred before the subtype split into two distinct clades (sometime in early 2005?), or they independently mutated with simultaneous Tamiflu resistance.  This "parallel development" theory is entirely plausible. 

But what if H1N1 was not the only virus that changed?  If H1N1 and H5N1 can get together this way, have they already gotten together before and spawned a mild H5N1 that is easily passed off as seasonal flu?  Again, Niman postulates that in Southeast Asia and in Egypt, there may be a mild form of H5N1 that is beginning to spread.  Now before we rejoice at the thought of a mild, nonlethal reassortant/recombinant H5N1, recall that in 1918, the second pandemic wave -- not the first wave -- was the murderer.  The first wave was passed off as normal, seasonal influenza.  Experts said, "No biggie; nothing to see here, folks." 

Of course, today's typing and surveillance is so much better, right?

If you say "Yes," then you didn't read my blog of yesterday.  Go get it: http://www.scottmcpherson.net/journal/2008/1/30/no-magic-bullets-to-fight-panflu.html

From today's AP story:

Drug-Resistant Flu Is Found in Europe

By MARIA CHENG

LONDON (AP) — A small number of flu viruses resistant to Tamiflu, a top antiviral drug, have been detected in Europe, health authorities said this week.

Data from more than a dozen European countries show that Tamiflu doesn't work in about 13 percent of H1N1 viruses, the main flu strain causing illness this year. Normally, resistance levels are well below 1 percent.

"It's an unexpected finding and a signal worth watching," said Fred Hayden, a flu expert at the World Health Organization. The resistant strains most likely emerged elsewhere, but were first identified in Europe.

The strain is resistant because of a single mutation. It doesn't cause more serious disease than regular strains, and can be treated with other antivirals. But experts are worried that if the resistance becomes widespread, Tamiflu, one of the best tools for fighting flu, might become useless.

"If I had only a single drug to choose for influenza, oseltamivir (Tamiflu) is the one I would go for," said Dr. Angus Nicoll, influenza coordinator for the European Centre for Disease Prevention and Control. Tamiflu, made by Roche Holding AG, has been stockpiled by WHO and by countries around the world for possible use in a flu pandemic.

But the resistant H1N1 strains do not mean that H5N1, the bird flu many experts fear could spark a flu pandemic, will develop similar resistance.

"The chance of this happening in an H5N1 virus is not zero, but probably very rare," said Dr. Joseph Bresee, chief of epidemiology and prevention at the United States' Centers for Disease Control and Prevention. At least two Tamiflu-resistant H5N1 strains have been found in Asia in the last few years.

Experts said that relying exclusively on Tamiflu is unwise. "This is a very good reminder that we don't know what the next pandemic strain will be sensitive to," Nicoll said. "Perhaps we should have more mixed antiviral stockpiles."

At the moment, health authorities are scrambling to find out how prevalent the resistant strain is worldwide. The highest levels have been found in Norway, where nearly 70 percent of tested strains have been resistant.

Resistance varies across Europe, with Italy reporting no resistant strains, and Britain, France and Denmark all reporting low but significant percentages.

In the United States, nearly 3 percent of tested flu samples have been resistant. "We don't know right now if this is a trend on the upswing or just a small blip," Bresee said.

Laboratories worldwide are also sequencing the mutated virus to try to determine where it came from and how it developed. Usually, resistant strains arise in people who have been treated with the drug. But that's not the case here.

In Norway, none of the viruses were from people who had been treated with Tamiflu. And in Japan, where Tamiflu use is the highest in the world, no resistant viruses have been reported this year. Investigations are ongoing in other countries.

Until now, experts had also believed that if viruses developed resistance, they would be less transmissible. "That assumption appears to have been incorrect," Hayden said.

As the flu season has only just started in Europe and North America, experts will be anxiously monitoring any further spread of the resistant H1N1 strains.

None of the other circulating human flu strains have so far been found to be resistant. Public health agencies say their recommendations on Tamiflu use remain unchanged.

It's still too early to know for sure what this means," Nicoll said. "But watch this space." (bold all mine)

Tamiflu resistance in seasonal influenza could thwart national pandemic plans

The cornerstone of most national pandemic preparedness plans revolves around the use of the antiviral drug Tamiflu, a neuraminidase inhibitor. Nations have been dutifully stockpiling the drug in massive quantities, keeping it in climate-controlled facilities guarded by armed military personnel.

But just as Hitler’s Wehrmacht took a Sunday drive around Belgium’s Maginot Line (pictured) in World War II, influenza appears to be ready to drive around the fixed fortifications of Tamiflu that have been constructed by national governments to combat an eventual influenza pandemic.

The Canadian Press’ Helen Branswell has written an excellent story on the sudden appearance of Tamiflu-resistant H1H1 across the European continent, as well as in Canada. The story appears at the bottom of the blog; but first, a little ru-ru (a punch line to a very, very funny joke).

We have known for years that H5N1 was slowly gaining Tamiflu resistance in some areas, most notably Egypt. We have also known that about 3% of Japanese seasonal Influenza B had shown some Tamiflu resistance.

What I don’t think we knew was that H1N1 was showing a markedly increased resistance to Tamiflu, and we did not know the CDC was actually tracking and cataloguing those resistance markers. Good for them; that is reassuring news. But if we are seeing a measurable, quantifiable increase in Tamiflu resistance in seasonal flu, we are doubtless able now to take a swag at the day that Tamiflu is no longer viable for influenza treatment of most – if not all – Type A influenzas.

Simply put: Tamiflu could go the way of Amantadine and Rimantadine, two antivirals that, once upon a time, went after the M2 protein outercoat of the flu virus, keeping it from dissolving  – until their effectiveness ran out and influenza A viruses became immune to the drugs.

The fact that Influenza A basically no longer responds to amantadine and rimantadine is unknown by a shockingly high number of American doctors, who apparently still get their updates on the effectiveness of medicine from the Saturday Evening Post. An excellent article from CIDRAP News details the unexplained continued mass prescription of M2-class antivirals to treat seasonal influenza by ignorant doctors – despite warnings from the CDC that such prescriptions are worthless. (Edited by me, the complete article can be found at: http://www.cidrap.umn.edu/cidrap/content/influenza/general/news/jan2408antivirals-jw.html

Older flu drugs still used, against CDC advice

Jan 24, 2008 (CIDRAP News) – A recent survey suggests that about a quarter of primary care physicians (PCPs) were still prescribing older antiviral drugs for influenza during the last flu season, despite a federal warning to avoid them because of viral resistance, according to the Centers for Disease Control and Prevention (CDC).

In the survey of 730 physicians in four states, 26.4% reported prescribing amantadine or rimantadine to some patients in the 2006-07 flu season, according to the report in the CDC's Morbidity and Mortality Weekly Report. In January 2006 the CDC recommended that physicians stop using the two drugs because of high rates of resistance in circulating strains of influenza A.

The survey also showed that 69% of physicians ordered influenza tests for patients with influenza-like illness (ILI), and most of those ordered rapid antigen tests. Because rapid tests miss up to 30% of flu cases, the CDC says, physicians should exercise clinical judgment when using them.

Antiviral prescriptions
About 54% of the physicians reported prescribing antiviral drugs to at least some patients, with the rates ranging from 41.7% for pediatricians to 66.4% for family practice.

The most commonly prescribed antiviral by far was oseltamivir (Tamiflu), a neuraminidase inhibitor, used by 87% of the respondents. The two older drugs, amantadine and rimantadine, were prescribed by 17.8% and 8.7%, respectively. Zanamivir (Relenza), the other licensed neuraminidase inhibitor, was prescribed by 5.3% of the physicians.

Amantadine use was highest in New Mexico (43.2% of doctors), followed by Minnesota (16.6%) and New York (14.2%), the report says. Respondents in Connecticut reported the highest use of oseltamivir (94.7%), followed by those in Minnesota (90.2%), New York (85.8%), and New Mexico (70.3%).

In light of the findings on antiviral prescribing, the CDC article calls for more education efforts to make PCPs aware of current treatment recommendations. The report also says that pediatric patients treated with oseltamivir should be watched closely for signs of neuropsychiatric effects, such as hallucinations, delirium, or abnormal behavior. Such effects have been reported in a number of young patients in recent years, mostly in Japan.

Influenza testing
A large majority—69%—of the responding doctors reported using a flu test during the flu season. The use of testing ranged from 87.1% of the Minnesota doctors to 55.0% of those in New Mexico. Of those who ordered tests, 88.0% used rapid antigen testing, 18.8% ordered viral culture, and 6.3% ordered serologic tests.

The CDC says many rapid antigen tests for flu can be handled by nonlaboratorians in office settings, which may explain why many physicians choose them. "However, the benefit of obtaining results quickly must be weighed against the low sensitivities of the tests (70%-75%)," the report says. Consequently, "PCPs should use clinical judgment and check reports of weekly influenza activity from CDC and their individual state health departments to guide their clinical decisions."

OK, so we know we need to slap some New Mexican doctors silly, plus a few in New York and Minnesota. We also know that only 69% of doctors everywhere are actually testing patients for influenza. Most of the 69% served up the rapid test, which is only 70% effective at diagnosis. So what that means is that out of every 100 people who suffer flu-like symptoms, only 69 are tested, and of those, only 48 have reliable test results. Someone in statistics test me on this, please.

It also means there are gaping holes in surveillance in this nation, when it comes to – well, when it comes to everything. We’re not testing properly for influenza. We’re not testing for MRSA. We’re not testing for adenovirus, especially Ad14. No wonder, then, that a Tamiflu-resistant H1N1 might crop up without anyone noticing!

There has always been a hunch among flu researchers that, in exchange for Tamiflu resistance, there might be a corresponding drop in a Tamiflu-resistant flu virus’s ability to transmit person-to-person. A quid pro quo, a “You scratch my nose and I’ll scratch yours,” a get-along-to-go-along virus mutation.

But as Lee Corso would say, “Not so fast, my friend!” The study, reported so well by Ms. Branswell, suggests that Tamiflu-resistant H1N1 is just as virulent and just as communicable as regular H1N1. So throw that theory out the window!

It is also quite interesting that while Tamiflu is encountering resistance via the position H274Y genetic marker (on the HA strand of RNA), Relenza, another neuraminidase inhibitor, is not suffering resistance. We know Relenza is essentially worthless as a treatment for severe H5N1, because you cannot inhale the drug deeply enough into the lungs to be effective. But as I have maintained over and over again, Relenza will make a dang skippy prophylactic against bird flu!

Nations, therefore, would do well to try and determine the prophylactic Relenza dosage for first responders and law enforcement types, and think seriously about expanding their Relenza strategery, as well as using Tamiflu to treat ill essential workers.

Tamiflu and Relenza are the only arrows in the quiver today to fight an eventual influenza pandemic. Other antiviral trials have failed recently (Bio-Cryst). Despite suggestions that science and medicine look to other strands in the flu’s RNA nucleus for disruption of the virus, precious little research has been done on that topic to date.

It is abundantly clear that Tamiflu’s life expectancy as an Influenza A inhibitor is finite. How finite that is requires extensive research and extensive data-gathering. It also means extensive surveillance and sample-collecting. So those county and state health departments need to be ready to gear up for a pretty huge swabbing effort.

All this points back to a quote that Dr. C. Everett Koop, former Surgeon General of the US, said last year.  He said: "We're fighting today's pandemic with the same tools we had 100 years ago." 

How about we drop this pretense of finding magic bullets, and just get on with the task of teaching hundreds of millions of people how to wash their hands correctly, how to cough or sneeze into their arm or sleeve or tissue, and how to keep a respectable distance from strangers?  Teaching these simple items is the absolute most cost-effective thing we can do  today.  Vaccines will be late to the dance and not reproducable until we have ID'ed the pandemic strain.  Antivirals will be iffy, depending upon when the pandemic strikes and whether the virus might have reassorted with a Tamiflu-resistant strain of existing Influenza A (although Egypt's Tamiflu-resistant H5N1 hasn't reassorted with a human strain that we are aware of, yet we know it is being given Tamiflu resistance from somewhere). 

Tamiflu-resistant flu viruses found in Canada

Provided by: Canadian Press
Written by: Helen Branswell, Medical Reporter, THE CANADIAN PRESS
Jan. 29, 2008

TORONTO - Canada's National Microbiology Laboratory is reporting a high level of Tamiflu resistance among H1N1 viruses circulating so far this flu season in this country, one of a number of labs to see a phenomenon that is unsettling influenza experts.

Nearly 10 per cent of H1N1 viruses tested so far this year by the Winnipeg lab are resistant to the drug, a cornerstone of pandemic planning for many countries around the globe. In the past, fewer than one per cent of circulating human flu viruses were thought to be resistant to Tamiflu.

"That's quite a surprise," the lab's scientific director, Dr. Frank Plummer, said, noting the resistance mutation spotted in the Winnipeg testing is the same one that has been reported over the past few days from Norway, several other European countries and the United States.

Eight of 81 H1N1 viruses tested carry the H274Y mutation - one each from British Columbia and Newfoundland and Labrador, and six from Ontario. Plummer said that total includes one virus (from British Columbia) recovered from a child who is believed to have been infected in Sudan.

His surprise is shared by experts with the World Health Organization's Global Influenza Program, which convened a teleconference of about 50 scientists from leading influenza laboratories around the world Tuesday to try to get a handle on how far this virus has spread, how common it is in places where it is being found and what is driving the spread.

Dr. Frederick Hayden, a leading antiviral expert working at the WHO, said the resistance virus has been reported over a broad geographic range, both in terms of countries and within countries themselves.

"We do know that again within the countries that have the information, it's not just focal pockets. There are multiple sites, for example, within France or within Norway where this has been detected," he said from Geneva.

The United States has reported that 5.5 per cent of tested H1N1 viruses there are resistant to the drug. European countries known to have found resistant viruses include Norway, Denmark, France and the United Kingdom. Hayden suggested more countries have found these viruses, but said he wasn't at liberty to name names.

Perplexingly, Japan - the country that uses more Tamiflu by far than any other in the world - has not found any of these resistant viruses this flu season, Hayden said.

Reports worldwide still number in the "few dozens." But that is enough to send up red flags, especially given that in all of the cases where details are known, people who caught the virus hadn't taken Tamiflu.

It wouldn't be startling to see people who've used the drug shedding viruses that are resistant to it. Like antibiotic resistance, resistance to antiviral drugs can develop in people who use them, though rates of drug-triggered resistance are low with Tamiflu.

But it had been thought that viruses that acquired this H274Y resistance mutation would pay for that gain with a corresponding loss in their ability to transmit. The belief was that if they developed in someone using Tamiflu, they would be unlikely to infect contacts of that person and start to circulate more widely - in essence, that they would be too weak to compete with regular flu viruses in the race to infect human respiratory tracts.

These recent findings suggest the drug is more vulnerable to the development of drug resistance than had been previously thought, experts fear.

"This mutation is not going to affect the fitness of the viruses as much as we thought," said Jennifer McKimm-Breschkin, a virologist with Australia's Commonwealth Science and Industrial Research Organization in Melbourne.

McKimm-Breschkin was one of the scientists involved in the discovery of Tamiflu's competitor, Relenza. Though the two drugs are in the same class, Relenza is still effective against viruses with the H274Y mutation.

"We're now seeing the ability of this virus that we thought would not have the ability to compete (with unmutated viruses) spreading globally," she said, suggesting that doesn't bode well if H5N1 avian flu starts a pandemic. The same mutation creates Tamiflu resistance in H5N1 viruses.

Hayden said the appearance of resistant H1N1 viruses across such a broad expanse "does raise a lot of questions."

Dr. Joe Bresee, chief of flu epidemiology and prevention at the U.S. Centers for Disease Control, questioned Monday whether there was a true rise in the number of resistant viruses.

Bresee cautioned that increased influenza surveillance prompted by concerns over the H5N1 virus may be turning a spotlight on something that always existed but went unnoticed in the past.

Hayden disagreed, saying an international network of antiviral experts has been watching for this resistance pattern but it has only been found rarely.

"Basically it was present at very low frequencies, less than a half per cent. In most studies, (it was) not even detected. So I think this is a new phenomenon and one that we need to understand better."

He said work is already underway to try to catalogue cases and to sequence resistant viruses to see if their genomes hold clues to how the resistance arose.